Should small renal masses be managed expectantly?

In this retrospective analysis the authors have studied the short-term outcomes of patients whose renal masses were managed expectantly (i.e., watchful waiting) to provide insight into the natural history of small renal tumors. This study also analyzed the effects of delayed intervention in patients who required intervention after a period of expectant management. A total of 43 patients with 46 renal masses underwent planned expectant management of enhancing solid or cystic (Bosniak IV) renal masses. A subset of these patients (13) who underwent eventual intervention was also examined. Outcomes with regard to age, gender, growth rate, subsequent interventions and clinical follow-up are reported. At a mean follow-up of 36 months 74% of patients had tumor growth with a mean (median) growth rate of 0.70 (0.35) cm per year. None of the patients had significant symptoms, disease progression or cancerspecific death. The 13 patients undergoing eventual intervention were younger than those who did not undergo intervention (56 vs. 72 years, respectively, P = 0.0006). Patients undergoing eventual intervention tended to have a higher tumor growth rate than those on continued observation (0.90 vs. 0.61 cm per year, respectively, P =0.1486). In patients undergoing eventual intervention 12 of 14 (87%) tumors were renal cell carcinoma. All were stage pT1 and 12 of 13 patients were alive after a mean follow-up of 41 months (one patient died of other causes 30 months after surgery). No patient had up-staging of disease secondary to delay.


SummARy
In this retrospective analysis the authors have studied the short-term outcomes of patients whose renal masses were managed expectantly (i.e., watchful waiting) to provide insight into the natural history of small renal tumors. This study also analyzed the effects of delayed intervention in patients who required intervention after a period of expectant management. A total of 43 patients with 46 renal masses underwent planned expectant management of enhancing solid or cystic (Bosniak IV) renal masses. A subset of these patients (13) who underwent eventual intervention was also examined. Outcomes with regard to age, gender, growth rate, subsequent interventions and clinical follow-up are reported. At a mean follow-up of 36 months 74% of patients had tumor growth with a mean (median) growth rate of 0.70 (0.35) cm per year. None of the patients had significant symptoms, disease progression or cancerspecific death. The 13 patients undergoing eventual intervention were younger than those who did not undergo intervention (56 vs. 72 years, respectively, P = 0.0006). Patients undergoing eventual intervention tended to have a higher tumor growth rate than those on continued observation (0.90 vs. 0.61 cm per year, respectively, P =0.1486). In patients undergoing eventual intervention 12 of 14 (87%) tumors were renal cell carcinoma. All were stage pT1 and 12 of 13 patients were alive after a mean follow-up of 41 months (one patient died of other causes 30 months after surgery). No patient had up-staging of disease secondary to delay.

CommenTS
In the present study small renal masses have been found to grow at an average rate of 0.70 and median of 0.35 cm per year, suggesting that smaller renal masses grow relatively slowly. The present study also attempts to identify factors that may be associated with more rapid growth rate. Interestingly, initial size and mode of presentation, symptomatic (28%) or asymptomatic did not correlate with growth rate in this population. Age was perhaps the strongest predictor of tumor growth, with younger patients (60 years old or younger) having more rapid growth rates.
There are several limitations to the present study. The follow-up period remains relatively short (approximately three years) which does not determine the long-term impact of a surveillance strategy. This is especially relevant for younger patients without significant co-morbidities. Accordingly, these results should not be taken as justification for observation of all renal tumors, especially in the younger, healthier patient.
This report represents a retrospective case series and not a prospective randomized surveillance trial. Thus, the findings are subject to potential selection biases that may affect the observed outcomes. For example, it is not surprising that those who underwent intervention had fewer co-morbidities and faster growth rates than those on continued observation, because such factors are likely to influence the decision to intervene. Similarly, it is conceivable that the co-morbid conditions (seen in 80% of patients in the surveillance group) could themselves potentially impact tumor biology and growth. Such questions remain unanswered in this and other retrospective reports.
Kassouf et al. [1] reported a growth rate of 0.49cm per year in their series of 24 patients. Chawla et al. [2] performed metaanalysis on natural history of renal masses and reported a mean growth rate of 0.28 cm yearly. This may be due in part to the presence of non-RCC pathologies and/or smaller tumor size in these studies. In another study of Gill et al. [3] 30% of the 100 tumors removed by laparoscopic partial nephrectomy were benign. Mean tumor size in this cohort was 2.8 cm. While it appears that the risk of malignancy is less in smaller lesions, the majority of these lesions are malignant with growth potential. 1.0% of patients in the meta-analysis population progressed to metastatic disease. interval of imaging the authors believe that it is prudent to have more frequent follow-up during the first 24 months.
Watchful waiting for renal masses is an appropriate option for select patients, especially those with competing comorbidities. Delayed intervention does not appear to adversely impact pathological outcomes. Younger patients may be more susceptible to rapid tumor growth and should be treated aggressively.

SummARy
This Phase 3 multicenter randomized trial [1] compared interferon alone, temsirolimus alone or the combination of both for the treatment of newly diagnosed metastatic renalcell carcinoma. From July 2003 to April 2005, a total of 626 patients were randomly assigned to one of the three study groups. Two hundred and seven were assigned to receive three million units of interferon alfa (with an increase to 18 million units subsequently) thrice weekly, 209 to receive 25mg of intravenous temsirolimus weekly and 210 to receive a combination of interferon and temsirolimus with 15mg of temsirolimus weekly plus six million units of interferon alfa thrice weekly. Those with histologically confirmed advanced renal-cell carcinoma (Stage IV or recurrent disease) and a Karnofsky performance score of 60 or more, with no previous systemic therapy and at least three of the six predictors of short survival were included. Patients were stratified according to the geographic location of the center and whether they had undergone nephrectomy. Treatment was continued as long as there was no disease progression, symptomatic deterioration or intolerable adverse events. Required imaging studies were done before treatment and were repeated at eight-week intervals to evaluate tumor size. The primary end point was overall survival, calculated on an intention-to-treat basis. This report was the second interim analysis conducted after 446 patients had died. Median survival was 7.3 months in the interferon group, 10.9 months in the temsirolimus group and 8.4 months in the combination therapy group and the median progression-free survival times in the interferon, temsirolimus and combination therapy groups were 1.9, 3.8 and 3.7 months, respectively. The objective response rates were 4.8%, 8.6% and 8.1% among patients receiving interferon, temsirolimus and combination therapy, not differing significantly. The effect of temsirolimus on overall survival was greater among patients under 65 years of age than among older patients and among patients with a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range than among those with lower levels.

CommenTS
Management of advanced renal-cell carcinoma (RCC) has made considerable progress in recent years and new emerging strategies are being developed. As distant metastases develop in about one-third of patients with RCC and most of these cases cannot be cured surgically, other options play an important role. Sunitinib, sorafenib and bevacluzimab have been proven to have efficacy in this scenario. [2] Both temsirolimus (CCI-779) and sirolimus (rapamycin), it s primary metabolite, are potent and specific inhibitors of the mammalian target of rapamycin (mTOR) kinase, involved in intracellular signaling pathways of cell proliferation. [3] Interleukin-2 and interferon alfa, alone or in combination, have been the main treatments for metastatic renal-cell carcinoma. In select groups treatment with these agents results in a median survival of 12.0 to 17.5 months. [4] They rarely benefit patients with an extensive tumor burden and adverse prognostic factors. It